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Graves' Disease in a Patient with Rheumatoid Arthritis During Treatment with Anti-Tumor Necrosis Factor-a To the Editor: In the last decade, blockade of tumor necrosis factor-a (TNF-a) has established itself as a new standard for treatment of rheumatoid arthritis (RA). In the late 1990s, the first clinical trials reported an impressive decrease in disease activity1. However, the initial mood of victory was tempered by several serious adverse events, mainly infections, among them tuberculosis2. In addition, some autoimmune conditions, such as lupus-like disease and multiple sclerosis3,4, were reported. Increasing knowledge of treatment-related adverse events resulted in an annually updated consensus statement2 and in pretreatment screening recommendations for tuberculosis5. Irrespective of this, longterm effects of anti-TNF-a are still not known, indicating that a continuous alertness for unexpected (rare) adverse events is warranted. We provide the first report of a patient who developed an autoimmune thyroid disease (ATD) during treatment with anti-TNF-a, 8 years after onset of treatment. In our outpatient clinic, a 70-year-old woman developed Graves' disease (GD) after an infectious episode, while being treated with anti-TNF-a for active RA. She had had RA since 1976 and was initially treated with conventional disease modifying antirheumatic drug (DMARD) therapy, which was discontinued because of inefficacy. She entered a clinical trial in 1998 with adalimumab, which soon proved to be highly effective. During this long period of treatment, she had a number of adverse events, the majority being pneumonias. In the beginning of 2006, she was treated with broad-spectrum antibiotics because of pneumonia in the right middle lobe, visible on a chest radiograph. After normalization of both the acute-phase response and chest radiograph, she did not recover completely and kept feeling ill and tired, without any clear signs or symptoms of another disease. Notably, the efficacy of the anti-TNF-a treatment was gradually decreasing for the last 6 months. Additional laboratory research indicated a significant hyperthyroidism [thyroid-stimulating hormone (TSH) < 0.010 mE/l (reference 0.4–4.0 mE/l); free T4 60.9 pmol/l (reference 8–22 pmol/l)]. Importantly, no thyroid nodules, palpitations, increased sweating, hair loss, exophthalmia, heat sensitivity, or irritability were reported upon history and examination. In the peripheral blood, antibodies against both thyroperoxidase [143 IE/ml (reference < 101 IE/ml)] and thyroglobulin [668 IE/ml (reference < 345 IE/ml)] were present, indicating an ATD. Thyroid scintigraphy revealed GD as the cause of the hyperthyroidism. She was treated with thiamazole (30 mg/day) and propranolol and improved clinically with a fully normalized TSH and free T4 within 4 months. Treatment with adalimumab was stopped, because of inefficacy in combination with recurrent infections. GD is one of the most common causes of hyperthyroidism. The development of GD is intriguing in our patient since she already had another autoinflammatory disease and was treated with anti-TNF-a. In the literature, the occurrence of ATD has been associated with RA6. However, no data are available on the relation with the treatment for RA. In our RA-comorbidity cohort7 (n = 1065), 4.6% of the patients (n = 49) had thyroid disease, including 1 patient with GD. This patient, however, had never been treated with anti-TNF-a before the onset of GD. In addition to RA, systemic lupus erythematosus, systemic sclerosis, Sjögren's syndrome, and poly/dermatomyositis have been reported to be associated with an increased prevalence of ATD6, suggesting an association of ATD with autoimmune diseases in general. The role of TNF-a in the pathogenesis of ATD is unclear. A potential role for TNF-a in GD has been suggested for Graves' ophthalmology based on histological examination8. Conflicting data have been reported on circulating TNF-a levels in GD during the disease course8-11. In our patient, we did not observe clear signs and symptoms that identified GD. This may be because the typical clinical picture of GD is absent in a number of patients. Another explanation could be that TNF-a blockade may mask clinical signs and symptoms, leading to underreporting. This hypothesis is in accord with a recent study in which a positive effect of 12 weeks of treatment with etanercept on Graves' exophthalmia is reported in 10 patients12. At the time the complaints of fatigue started in our patient, secondary inefficacy to anti-TNF-a treatment was developing, potentially due to formation of human anti-human antibodies. This might have resulted in an altered balance of the immune system, allowing GD to develop. More knowledge on the role of TNF-a in GD is needed to reveal how anti-TNF-a might have contributed to the development of GD in this case. Ours is the first report of a patient diagnosed with GD during anti-TNF-a treatment. Whether there is a relationship between symptoms of GD and anti-TNF-a remains uncertain. This case once more indicates that thorough monitoring of patients who are treated with anti-TNF-a should be emphasized. ANTOINE W.T. van LIESHOUT, MD; MARJONNE C.W. CREEMERS, MD, PhD, Department of Rheumatology; TIMOTHY R.D.J. RADSTAKE, MD, PhD, Departments of Rheumatology and General Internal Medicine; LAMMY D. ELVING, MD, PhD, Department of General Internal Medicine; PIET L.C.M. van RIEL, MD, PhD, Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Address reprint requests to Dr. M. Creemers, UMC St. Radboud 470 Rheumatology Geert, Grooteplein 8, 6500 HB Nijmegen, The Netherlands. E-mail: m.creemers@reuma.umcn.nl
We thank W. Kievit (Rheumatology, UMCN, Nijmegen) for collecting the clinical data from our prospective cohort database, and R. Rambaratsingh (Abbott, The Netherlands) for retrieving serum samples for determination of thyroid antibodies. We thank I. Klasen and J. Goërtz (ABTI, UMCN, Nijmegen) for measuring antibodies. 2. Hyrich KL, Silman AJ, Watson KD, Symmons DP. Anti-tumour necrosis factor alpha therapy in rheumatoid arthritis: an update on safety. Ann Rheum Dis 2004;63:1538-43. [MEDLINE] 3. Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 2001;44:2862-9. [MEDLINE] 4. Shakoor N, Michalska M, Harris CA, Block JA. Drug-induced systemic lupus erythematosus associated with etanercept therapy. Lancet 2002;359:579-80. [MEDLINE] 5. Furst DE, Breedveld FC, Kalden JR, et al. Updated consensus statement on biological agents, specifically tumour necrosis factor-a blocking agents and interleukin-1 receptor antagonist, for the treatment of rheumatic diseases, 2005. Ann Rheum Dis 2005;64 Suppl:iv2-14. 6. Biro E, Szekanecz Z, Czirjak L, et al. Association of systemic and thyroid autoimmune diseases. Clin Rheumatol 2006;25:240-5. [MEDLINE] 7. Welsing P, Van Riel P, Fransen J, Kievit W. The relation of disease activity and methotrexate with the risk of cardiovascular disease in patients with rheumatoid arthritis [abstract]. In: Program, European League Against Rheumatism 2005 Annual Scientific Meeting; June 8-11, 2005; Vienna, Austria. Abstract OP0103. 8. Avunduk AM, Avunduk MC, Pazarli H, et al. Immunohistochemical analysis of orbital connective tissue specimens of patients with active Graves ophthalmopathy. Curr Eye Res 2005;30:631-8. [MEDLINE] 9. Celik I, Akalin S, Erbas T. Serum levels of interleukin 6 and tumor necrosis factor-alpha in hyperthyroid patients before and after propylthiouracil treatment. Eur J Endocrinol 1995;132:668-72. [MEDLINE] 10. Chopra IJ, Sakane S, Teco GN. A study of the serum concentration of tumor necrosis factor-alpha in thyroidal and nonthyroidal illnesses. J Clin Endocrinol Metab 1991;72:1113-6. [MEDLINE] 11. Diez JJ, Hernanz A, Medina S, Bayon C, Iglesias P. Serum concentrations of tumour necrosis factor-alpha (TNF-alpha) and soluble TNF-alpha receptor p55 in patients with hypothyroidism and hyperthyroidism before and after normalization of thyroid function. Clin Endocrinol 2002;57:515-21. [MEDLINE] 12. Paridaens D, van den Bosch WA, van der Loos TL, Krenning EP, van Hagen PM. The effect of etanercept on Graves' ophthalmopathy: a pilot study. Eye 2005;19:1286-9. [MEDLINE]
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